This invention relates to the production of fibers of linear poly(ethylenimine) modified with nitric oxide (NO). More particularly, the present invention relates to the use of these NO-modified linear poly(ethylenimine) fibers that can be applied to medical devices such as catheters, stents, vascular grafts, wound dressings, and the like, to release therapeutic levels of NO for wound healing or other medical purposes. Specifically, the present invention relates to the production of electrospun nanofibers of linear poly(ethylenimine) diazeniumdiolate for use in the delivery of NO to a patient.
The importance of nitric oxide (NO) in biological repair mechanisms is well known even though the precise mechanism of its action has not been completely elucidated. NO is known to inhibit the aggregation of platelets and to reduce smooth muscle proliferation, which is known to reduce restenosis. When delivered directly to a particular site, it has been shown to prevent or reduce inflammation at the site where medical personnel have introduced foreign objects or devices into the patient.
Researchers have sought various ways to deliver NO to damaged tissue and to tissues and organs at risk of injury. NO can be delivered systemically, but such delivery can bring undesired side effects with it. Ideally, NO should be delivered in a controlled manner specifically to those tissues and organs that have been injured or are at risk of injury. Various compounds have been used to deliver NO therapeutically. Diazeniumdiolates (NONOates) exhibit the ability to release NO spontaneously. Other classes of NO donors either require activation to release therapeutic levels of nitric oxide, or they release both NO and undesired free radicals.
The use of NONOates for the release of nitric oxide to specifically treat tissue that has been injured or is at risk of injury during sepsis or shock has been described in at least Saavedra et al. U.S. Pat. No. 5,814,656, the disclosure of which is incorporated herein by reference. Insoluble polymeric NONOates have also been generally described in Smith et al. U.S. Pat. No. 5,519,020, the disclosure of which is also incorporated herein by reference. These polymers were used to deliver NO to specific tissues, and results have shown that controlled release of NO to a specific site greatly reduced the inflammation and accelerates the healing process at that site. However, heretofore, these compositions have had to be delivered either by topical application or by coating onto the medical device. While such applications have been successful, the need continues to exist to provide a manner in which the NONOate compositions could be exposed to a greater surface area of the medical devices to which they are applied. The use of NONOates as coatings on implantable medical devices is also disclosed in Stamler et al. U.S. Pat. No. 5,770,645, the disclosure of which is also incorporated herein by reference.
In addition to the need set forth hereinabove, the process of coating some medical devices, particularly implantable devices, may have adverse effects on and alter the physical properties of the device. This can contribute to serious complications from the body""s own defense to the medical device as foreign material.
The technique of electrostatic spinning, also known within the fiber forming industry as electrospinning, of liquids and/or solutions capable of forming fibers, is well known and has been described in a number of patents as well as in the general literature. The process of electrostatic spinning generally involves the introduction of a liquid into an electric field, so that the liquid is caused to produce fibers. These fibers are generally drawn to a cathode for collection. During the drawing of the liquid, the fibers harden and/or dry. This may be caused by cooling of the liquid, i.e., where the liquid is normally a solid at room temperature; by evaporation of a solvent, e.g., by dehydration (physically induced hardening); or by a curing mechanism (chemically induced hardening).
Fibers produced by this process have been used in a wide variety of applications, and are known, from U.S. Pat. Nos. 4,043,331 and 4,878,908, the disclosures of which are incorporated herein by reference, to be particularly useful in forming non-woven mats suitable for use in wound dressings and prosthetic devices. One of the major advantages of using electrostatically spun fibers is that these fibers can be produced having very thin diameters, usually on the order of about 100 nanometers to about 25 microns, and more preferably, on the order of about 100 nanometers to about 1 micron. Thus, these fibers can be collected and formed into coatings or non-woven membranes of any desired shape and thickness. It will be appreciated that, because of the very small diameter of the fibers, the resultant coating or membrane will have very small interstices and high surface area per unit mass.
Linear poly(ethylenimine) (L-PEI) is known to be a water insoluble polymer, but soluble in alcohols and other organic solvents. In order to electrospin fibers, the polymer must first be in liquid form (i.e., soluble). However, in order to be useful as a NO-releasing complex, the polymer must be capable of being converted to a diazeniumdiolate (NONOate) and should be insoluble in all solvents once formed.
Thus, the need exists for a method for coating or otherwise depositing diazeniumdiolate-modified fibers, and particularly, linear poly(ethylenimine) fibers, onto medical devices in a manner which suitably provides for the release of therapeutic amounts of NO to a particular site.
It is, therefore, an object of the present invention to provide a medical device comprising at least one nanofiber of a polymeric nitric oxide donor that forms a coating layer on the device.
It is another object of the present invention to provide a medical device comprising at least one nanofiber of a polymeric diazeniumdiolate derivative that forms a coating layer on the device.
It is yet another object of the present invention to provide a medical device comprising at least one nanofiber of linear poly(ethylenimine) diazeniumdiolate derivative that forms a coating layer on the device.
It is still another object of the present invention to provide a medical device comprising at least one nanofiber, wherein the nanofibers provide a greater surface area to unit mass ratio than ordinary topical coatings.
It is still another object of the present invention to provide at least one nanofiber, as above, which is capable of being coated or otherwise applied to medical devices.
It is a further object of the present invention to provide a medical device, as above, wherein the device is coated with at least one electrostatically spun nanofiber of a polymeric nitric oxide donor.
It is still another object of the present invention to provide an improved medical device, as above, wherein the device is coated with nanofibers of crosslinked linear poly(ethylenimine) diazeniumdiolate.
It is yet another object of the present invention to provide an improved medical device, as above, wherein the electrostatically spun nanofibers are directly spun onto the medical device.
It is still another object of the present invention to provide a method of making a medical device comprising at least one nanofiber of linear poly(ethylenimine) forming a coating layer on the device.
In general, the present invention provides a method for the production of at least one fibers of linear poly(ethylenimine) diazeniumdiolate using electrospinning techniques. Such fibers have very small diameters of less than 1 micron, and, more preferably, less than 400 nanometers. The fibers also have very high surface areas per unit mass and are capable of releasing therapeutic levels of NO as needed.
Other aspects of the present invention are achieved by a coating for a medical device comprising at least one electrospun fibers of linear poly(ethylenimine) diazeniumdiolate. A coating containing these fibers has a much larger surface area per unit mass than do topical coatings previously employed, and have minimal effect to the properties of the medical devices employed. The fiber-coated medical devices are capable of releasing therapeutic levels of nitric oxide to a particular site of a patient.
The present invention further provides a medical device having at least one electrospun fibers comprising a polymeric NONOate deposited thereon. Such medical devices may include catheters, stents, vascular grafts, wound dressings, and other related medical devices which may be implanted or otherwise invade a patient""s body.